Ulm, Univ. Diss., 2005.

Ulm, Univ., Diss., 2008.

The Master thesis gives an overview of sepsis, its causes, manifestation and diagnostics. The role of procalcitonin as a sepsis marker is dicussed. In the experimental part, case records of 106 were examined and the determination of procalcitonin as a sepsis marker was evaluated. Based on the evaluation, a recommendation about timing of the procalcitonin level analyses with septic patients were made.

Class of 2015 Abstract / Objectives: To (1) characterize loading doses of vancomycin administered to patients with sepsis and (2) evaluate the relative impact of loading dose on clinical outcomes between patients who received a 1 gram loading dose or any other amount. Methods: Retrospective, observational chart review of adult patients who received vancomycin for treatment of sepsis through emergency department triage. Data from November 2013 through March 2014 were obtained for timing and administration of vancomycin as well as clinical outcomes: survival; length of hospitalization and intensive care unit (ICU) stay; need for mechanical ventilation. Results: Sepsis-related hospital encounters were identified for 123 patients, of which 114 charts were fully able to be evaluated. The majority of patients (84.21%) received a 1 gram loading dose as opposed to any other amount (p=0.001); few patients (1.75%) received a dose within 25-30 mg/kg. No significant differences in trends for timing of administration, inpatient survival, duration of hospital stay, or need for mechanical ventilation were identified between patients who received 1 gram doses or any other amount. Greater effective vancomycin loading doses were associated, albeit not significantly, with shorter durations of hospitalization, ICU admissions, and mechanical ventilation. Conclusions: Despite weight-based loading dose recommendations, vancomycin was frequently administered as a fixed 1 gram loading dose to patients with sepsis. However, there was little distinguishable impact on clinical outcomes in this preliminary study.

Bakgrund: Sepsis är ett globalt hälsoproblem ibland jordens befolkning. 49 miljoner drabbas runt om i världen och de patienter som överlevt riskerar att få komplicerade komplikationer som följd. Det innebär att de drabbade är i behov av hjälp och stöd för att kunna ta sig tillbaka till det vardagliga livet. Syfte: Syftet är att belysa hur eftervården upplevs av individer som drabbats av sepsis. Metod: Studien är en empirisk enkätstudie som analyserades med kvalitativ innehållsanalys. Informanterna kontaktades via ett sepsisforum på Facebook och även kontakter via sepsisfonden. Informanterna besvarade fyra frågor som berörde upplevelsen av eftervården. Resultat: Resultatet består av fyra olika teman: Frånvaro av uppföljning, försummad av vården, kunskapsbrist i vården och god vårdkontakt. Utifrån informanternas egna ord i studien, som beskriver individernas egen upplevelse av eftervården, kunna få en ökad förståelse om det finns positiva eller negativa erfarenheter om eftervården. Slutsats: Vården har ett ansvar att guida, informera och följa upp patienterna på bästa sätt. / Background: Sepsis has become a global health problem among the population in the world, about 49 million people are affected around the world. The patients who have survived are at risk of getting complications. This means that some people need care and support to be able to go back to their normal life. Aim: The purpose of the study is to illustrate how the aftercare is experienced by individuals affected by sepsis. Method: The study is made of a qualitative content analysis with a questionnaire. Participants were contacted on a sepsis-forum on Facebook and sepsis foundation. Participants answered four questions that concerned the experience of aftercare. Choice of method and analysis produced four themes that form the basis for the results. Result: The result is made of four different themes: Lack of follow-up, neglected by care, lack of knowledge care and god care. The study is based on the informant’s own words, which describe the people's own experience of aftercare, to gain an increased understanding of whether there are positive or negative experiences about aftercare. Conclusion: The healthcare system has a responsibility to educate, guide and follow up this group.

Introducción: La sepsis neonatal temprana es un cuadro clínico caracterizado por manifestaciones de infección sistémica que aparece en las primeras 72 horas de vida, en México se encuentran tasas de entre 0.76 y 4.7 por 1000 nacidos vivos, con una letalidad de entre 5.7% y 9%. Objetivos: Determinar las características clínicas de los recién nacidos con sepsis neonatal temprana en el Hospital Nacional Dos de Mayo durante el 2015. Diseño: Estudio descriptivo. Lugar: Hospital Nacional Dos de Mayo. Participantes: Pacientes del servicio de Neonatología diagnosticados con sepsis neonatal temprana posible, probable y confirmada. Intervención: Recolección de datos a través de la base de datos de los pacientes del servicio de Neonatología y revisión de historias clínicas. Resultados: Se incluyeron 479 pacientes, 5.4% fueron confirmados con hemocultivo. 85.4% fueron neonatos a término, el 75.8% tuvo adecuado peso al nacer. El factor de riesgo más frecuente fue la ITU en el tercer trimestre del embarazo. La ictericia fue el signo más común y la PCR > 10 mg/dL el hallazgo de laboratorio más frecuente. El estafilococo coagulasa negativo fue el patógeno aislado en la mayoría de casos. 0.83% del total pacientes fallecieron. Conclusiones: La frecuencia de sepsis neonatal temprana confirmada en el Hospital Nacional Dos de Mayo en el 2015 fue de 9 por 1000 nacidos vivos, la tasa de letalidad fue de 11.5% Palabras clave: Sepsis, neonato, factores de riesgo, signos clínicos, letalidad. / --- Introduction: Early-onset neonatal sepsis is a clinical syndrome characterized by manifestations of systemic infection that appears in the first 72 hours of life, in Mexico there are rates between 0.76 and 4.7 per 1000 newborns, with a lethality rate between 5.7 and 9%. Objective: To determinate the clinical features of newborns with early-onset neonatal sepsis in the Dos de Mayo National Hospital during 2015. Design: Descriptive study. Place: Dos de Mayo National Hospital. Participants: Patients from the Neonatology service diagnosed with possible, likely and confirmed early-onset neonatal sepsis. Intervention: Data collection through the Neonatology service patients’ database and clinical record review. Results: 479 patients were included, 5.4% were confirmed by blood culture. 85.4% were term infants, 75.4% had adequate birth weight. The most frequent risk factor was the UTI in the third trimester of pregnancy. Jaundice was the most common sign and CRP > 10 mg/dL the most frequent laboratory finding. Coagulase negative Staphylococcus was the most common insolated pathogen. 0.83% of the patients passed away. Conclusions: The frequency of confirmed early-onset neonatal sepsis in the Dos de Mayo National Hospital during 2015 was 9 per 1000 newborns, the lethality rate was 11.5%. Key words: Sepsis, newborn, risk factor, clinical sign, lethality. / Tesis

Bakgrund: Sepsis definieras som en kroppslig reaktion på infektion och klassificeras som ett livshotande medicinskt tillstånd. Post-sepsis kännetecknas av hög mortalitet och morbiditet samt svår återhämtning. Därför är det viktigt att identifiera och sammanställa de problem patienter träffar på efter sepsis vård genom att bedöma deras livskvalitet efter sepsis. Syfte: Syftet med studien var att beskriva skillnader i livskvalitet efter genomgången sepsis, vid olika tidpunkter och i jämförelse med andra grupper i befolkningen. Metod: Litteraturstudien innefattar åtta empiriska studier med kvantitativ metod och sökning gjordes i databaserna Pubmed och Cinahl. Artiklarna kvalitetsgranskades, analyserades och sammanställdes i text och tabeller. Resultat: Artiklarna använde olika mätinstrument som inkluderar Short-Form Health Survey (SF-36), EuroQol-5 Dimensions (EQ-5D) och Sickness Impact Profile (SIP).Domänerna i mätinstrumentet omgrupperades för att anpassa resultaten till varandra och SF-36 användes som grundparametrar. Deltagarna upplevde ett signifikant nedsatt fysiskt och psykisk förmåga efter genomgången sepsis. Konklusion: Sepsis är en livshotande sjukdom som visade sig ha en hög grad påverkan på patienternas fysiska och mentala livskvalitet, under en lång period och återhämtning kan vara svår. Detta innebär att sepsis överlevande behöver vård under sjukhusvistelse samt även efter utskrivning. Ökad förståelse och kunskap behövs för att främja insatser som lindrar samt förbättrar livskvalitet hos sepsis överlevande. / Background: Sepsis is defined as a disturbed bodily reaction to infection and is classified as a life-threatening medical condition. Post-sepsis is characterized by high mortality and morbidity as well as difficult recovery. Therefore, it is important to identify and compile the problems patients encounter after sepsis care by assessing patients’ quality of life after sepsis. Aim: The purpose of the study was to describe differences in quality of life after surviving sepsis, at different times and in comparison, with other population groups. Methods: The literature study contains eight empirical studies with quantitative methods found in Pubmed and Cinahl. The articles were cross-examined, analyzed, and compiled in text and tables. Results: The articles used various quality-of-life measuring instruments that include the Short-Form Health Survey (SF-36), EuroQol-5 Dimensions (EQ-5D) and the Sickness Impact Profile (SIP). The domains in the measuring instrument were regrouped, and domains from SF-36 were used as base parameters. Patients experienced impaired physical and mental ability after sepsis. Conclusion: Sepsis is a life-threatening disease that has been shown to have a high degree of impact on patients’ physical and mental quality of life over a long period of time, and recovery can be difficult. This shows that sepsis survivors need care during the hospital stay and after discharge. Increased understanding and knowledge are needed to promote efforts that alleviate and improve the quality of life of sepsis survivors.

Sepsis is an immunological condition defined by a pathogen inducing the Systemic Inflammatory Response Syndrome (SIRS), which itself is a clinical diagnosis involving temperature, heart rate, respiration, and white blood cell (WBC) count. Our lab uses Cecal Ligation and Puncture (CLP) to induce polymicrobial sepsis in mice, with a mortality rate of 50 percent. Previous research in our lab has demonstrated that the plasma levels of IL-6 collected six hours after the start of sepsis can be used to predict which mice will live (Live-P) and which mice will die (Die-P) during the acute phase (<5 days post CLP). This predictive tool enables stratification of mice prior to mortality to determine immunological differences between groups. With this approach it was found that both Live-P and Die-P mice have equivalent bacterial burden and phagocyte recruitment within 6 hours of CLP. Yet by 24 hours, Die-P mice have increased bacterial burden while recruiting more phagocytes than Live-P. This suggested a phagocytic impairment. This study reproduced the aforementioned findings and subsequently determined that Die-P peritoneal phagocytes kill fewer bacteria than Live-P. This bactericidal deficit was associated with multiple cellular defects. The reduced cellular function included: decreased phagocytosis, decreased phagosomal acidification, and decreased generation of reactive oxygen species (ROS). All of these are integral components of the bacterial killing process. Furthermore, it was found that this deficit was due to cellular suppression and not to cellular exhaustion. The study of phagocytic function was then extended to the bone marrow, a source of phagocytes, and to the peripheral blood. Die-P bone marrow phagocytes showed increased phagocytic activity despite a similar capacity to respond to bacteria as Live-P. Additionally, Die-P bone marrow phagocytes were found to express higher levels CD11b, a marker of activation. Conversely, Die-P peripheral blood phagocytes expressed higher levels of activation markers while exhibiting decreased phagocytic functions. This study then recapitulated the phagocytic dysfunction of septic cells with naïve healthy cells. A surge in pro and anti-inflammatory mediators is a hallmark of sepsis, with Die-P mice producing a significantly larger surge. Naïve phagocytes were incubated with plasma or peritoneal fluid from Live-P and Die-P mice and it was found that Die-P fluids significantly compromised the phagocytic activity of naïve phagocytes. These studies collectively suggest that mortality from CLP induced sepsis is due to failure to kill bacteria and that differential production of inflammatory mediators contributes to the differences in phagocytic function.

Sepsis is a devastating clinical condition characterized by a systemic inflammatory response to infection, with concomitant dysregulated pathological thrombus formation. Although sepsis is triggered by the release of microorganisms and/or microbial toxins into the circulation, the presence of infection itself is rarely the cause of death in these patients. Rather, mortality in sepsis is attributed to irreversible organ damage resulting from prolonged, uncontrolled activation of inflammatory and coagulation pathways within the microcirculation. Despite recent advances in clinical management, treatment continues to be largely supportive in nature. As a result, sepsis remains the leading cause of morbidity and mortality in non-coronary intensive care units with mortality rates ranging from 18-30%. Sepsis-induced mortality is further increased following the development of disseminated intravascular coagulation, a thrombohemorrhagic state defined by a primary thrombotic and secondary hemorrhagic diathesis that may culminate in multi-organ failure. Clinical management of patients with sepsis is challenging and largely limited to supportive therapies, which is in part related to a limited understanding of the underlying pathophysiology. Recently, cell-free DNA (CFDNA) has emerged as an important link between innate immunity, coagulation, and inflammation. Furthermore, we have previously demonstrated that plasma levels of CFDNA have high discriminative power to predict ICU mortality in patients with severe sepsis. Patients with higher plasma concentrations of CFDNA are more likely to face severe complications such as organ dysfunction/failure, and death. The evidence presented in this thesis suggests that CFDNA may not simply be an innocuous marker of disease severity, but may itself exert pathological effects and contribute to the fatal coagulation abnormalities observed in sepsis patients. / Thesis / Doctor of Philosophy (PhD)

Given the current obesity epidemic, the prevalence of overweight and obese patients with critical illness is increasing rapidly, however how obesity shapes critical illness and immune response to infection is not entirely understood. We developed a clinically relevant murine model of obesity in the context of sepsis, and examined organ specific inflammatory responses. Male C57BL/6 mice were fed either a high fat Western Diet (WD) (Modified Breslow, 21% Butterfat and 0.15% cholesterol) or normal chow diet (NCD) for 6, 15 or 27 weeks. Sepsis was induced by cecal ligation and perforation (CLP), and six hours post-surgery, plasma and tissue samples were harvested and flash frozen in liquid nitrogen. Septic obese mice at 15 and 27 weeks had significantly (p<0.0001) lower levels of lung myeloperoxidase (26.3±3.8 U/mg tissue) compared to age matched ad libitum (44.1±2.8 U/mg tissue) and diet restricted (63.2±5.60 U/mg tissue) controls, indicative of less lung inflammation. Obese mice (4.23±0.10g) had significantly enlarged livers compared to controls (1.55±0.80g and 1.22±0.031g), with pronounced steatosis, and hepatocyte ballooning, independent of sepsis. These findings are in congruence with clinical observations that obese individuals are protected from sepsis-induced lung injury, however the mechanisms involved are not entirely clear. We also examined effects of housing conditions on susceptibility to developing metabolic syndrome, and inflammatory response in our obesity and sepsis model. For this study, animals were fed either WD or NCD for 15 weeks and were housed in static or ventilated cages. Unlike static cages, ventilated cages have HEPA filtered air supply system and exhaust air ventilation, protecting the animals from air borne particles and preserving the microbiological barrier. Therefore, ventilated cages provide a more sterile environment compared to static cages. After 15 weeks, fecal matter was collected from the cages and mice were subjected to sepsis using the CLP technique. Six hours post surgery, animals were sacrificed and tissues were harvested, snap frozen and stored at -80°C. The animals from the more sterile environment (ventilated cages) had significantly (p<0.0001) less weight gain and did not show signs of overt hyperglycemia, compared to mice housed in a less sterile environment (static cages). In addition, obese mice housed in static cages had less lung injury compared to controls during early sepsis, however this difference was not evident in mice from ventilated cages. There were also significant differences in the fecal microbe composition, where ventilated groups had greater Firmicutes (69% ± 0.06% for WD and 76% ± 0.03%) and less Bacteroidetes population (15% ± 0.04% for WD and 12% ± 0.02% for NCD) compared to static groups (Firmicutes: 42% ± 0.08% for WD and 24% ± 0.02% for NCD, Bacteroidetes: 37% ± 12% for WD and 53% ± 29% for NCD). This study highlighted the impact of environment on the susceptibility to developing metabolic syndrome, and the potential impact on the associated immune responses, in our mouse models of obesity and sepsis. Leptin is an important mediator of immune responses to infection, and the levels are elevated during diet induced obesity in both mice and humans. We found that mice treated with leptin one hour prior to surgery, had significantly less injury (32.62±1.6 U/mg tissue) compared to saline treated animals (46.58±3.48 U/mg tissue), as evident from lung myeloperoxidase levels and histopathology scores. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) over expressing mice on a normal diet, had significantly greater lung injury (46.51±4.51 U/mg tissue myeloperoxidase levels) compared to knockouts (31.14±1.75 U/mg tissue), this difference was not observed in WD fed mice with differential PCKS9 expression. In conclusion, WD fed mice had significantly less lung inflammation but greater hepatic injury. Furthermore, both leptin and PCSK9 are important mediators of lung inflammation in early sepsis. / Thesis / Doctor of Science (PhD)